Skeletal development in humans is regulated by numerous growth factors.
Among them Fibroblast Growth Factor Receptor 3 (FGFR3) has been described as a negative regulator of endochondral ossification. Mutations in the gene encoding for the FGFR3 have been shown to be responsible for the phenotype of numerous skeletal chondrodysplasias (1), including the thanatophoric dysplasias (TDI and TDII) (2) and achondroplasia (3), the most common form of short limb dwarfism. Children affected by achondroplasia suffer from deformations of the skull and vertebrae and abnormal long bone development, resulting in short stature and severe neurological and orthopedic complications (4, 5). Existing treatments are only designed to alleviate some of the complications, and are invasive and extreme (6, 7).
Achondroplasia is an autosomal dominant disorder caused by a point mutation in the gene for FGFR3 (Fgfr3ach) (8). In ˜97% of affected patients, achondroplasia is caused by a G380R substitution in the transmembrane domain of the receptor (9, 10). This mutation in FGFR3 results in a gain of function (11), which prolongs activation of the tyrosine kinase activity of the receptor (12, 13). The G380R mutant FGFR3 remains ligand dependent for its dimerization and activation (12, 14); however, the presence of the mutation stabilizes the ligand/receptor complex (15) and slows down receptor internalization (12), thus extending subsequent intracellular Ras/MAPK pathway signaling (12). The resultant FGFR3 signaling is prolonged and steadily inhibits chondrocyte proliferation and differentiation in the growth plate (16). Cells expressing the mutant receptor do not mature and are not replaced by mineralized bone matrix, impairing lengthening of all bones formed by endochondral ossification (17, 18). These include the long bones of the appendicular skeleton, as well as the vertebrae, sternum, cranial base, and some bones in the skull where bone growth occurs at synchondroses, which are cartilaginous structures consisting of two opposed growth plates with a common zone of resting chondrocytes. As with endochondral growth plates in the long bones, synchondroses also become replaced by bone.
Despite an increased number of studies deciphering the mechanisms responsible for bone growth disturbances, there is still no cure available. Several therapeutic strategies are considered targeting mutant FGFR3 and its downstream signaling (16). Recently, Jin et al. have tested a novel peptide inhibiting FGFR3 signaling in a murine model of TDII (19). This study shows reversion of the neonatal lethality of TDII mice following in utero treatment and demonstrates the proof-of-concept that targeting FGFR3 in the extracellular compartment may be an effective strategy to treat FGFR3-related skeletal dysplasias.
Current therapies of achondroplasia include orthopedic surgeries such as leg lengthening and growth hormone therapy. However, leg lengthening inflicts a great pain on patients, and growth hormone therapy increases body height by means of periodic growth hormone injections starting from childhood. Further, growth ceases when injections are stopped. Consequently, it is desirable to develop a new achondroplasia therapy, as well as other skeletal growth retardation disorders including FGFR3-related skeletal diseases.